Over the past two decades, the promise of accelerated drug development and personalized medicine have brought heighten attention to the field of biomarker. But do you really know what biomarker are, how they are developed, and how they are used?
Here, I'll share over 15 years of experience in the fields of biomarker development and translational research to try to answer some of these questions.

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Friday, October 7, 2011

In the
early online issue of the Proceedings of the National Academy of Sciences of
October 3rd (link),
Hu and colleagues reports on a new biomarker of disease activity for
Huntington’s disease (HD) based on the
differential expression level of the transcript for H2AFY gene
in peripheral blood mononuclear cells (PBMC). HD is an autosomal recessive genetic disorder in
which nerve cells in certain parts of the brain waste away, or degenerate.

Similarly
to the recent work on ALS biomarkers published in PLoS One this month (see
earlier post: New
Potential ALS Multiprotein Biomarker: Going Beyond Nerve Pathology), Hu et
al. hypothesized that the key pathobiology affecting neurons in HD would be
detectable in other cell types than neurons.
Indeed, the huntingtin protein, which has been shown to be at the center
of HD pathobiology, is expressed in most tissues, including PBMC.

Using
a standard transcriptomics approach, the authors surveyed the entire genome for
differential RNA expression between the PBMC of HD patients, healthy controls,
and other neurological disorders (Parkinson’s disease, Alzheimer’s disease,
corticobasal degeneration, essential tremor, progressive supranuclear palsy,
and multiple system atrophy). Using
stringent statistical criteria and pathobiological knowledge, the team selected
the transcriptional modulator H2A histone family member Y (H2AFY) as the most
relevant biomarker for HD. This initial
discovery was confirmed by two independent studies. First, a cross-sectional case controlled
study of an additional 36 HD patients, 9 carriers of the HD mutation with no
clinical symptoms (the HD mutation has 100% penetrance and therefore all
carriers will eventually develop the disease), 50 healthy controls, and one
individual with spinocerebellar ataxia.
Second, a longitudinal case-control study where 25 HD patients and 21
healthy controls were followed for at least 2 years (37 subjects were followed
for 3 years).

In order
to link the transcriptional difference observed in PBMC of HD patients to the
pathobiology of the disease, the authors analyzed the expression of the
H2AFY-encoded protein MacroH2A1
in the frontal cortex of postmortem brains obtained from 12 HD patients. While the expression of MacroH2A1 was clearly
elevated in the brain of patients with grade 2 or 3 disease, this trend was not
maintained in grade 4 patients. This was
most likely due to the fact that MacroH2A1 is expressed at high level in
neurons and that this stage of the disease is characterized by a substantial
loss of these cells. Finally, the authors assessed
the translational value of the H2AFY / MacroH2A1 biomarker in a mouse model of
HD (knock-in of exon 1 fragment of the human huntingtin gene). There again, the progression of the disease
was associated with an elevation of the MacroH2A1 protein in relevant brain
substructures and treatment with the experimental HDAC inhibitor sodium
phenylbutyrate resulted in a decrease in the biomarker signal.

Altogether,
if these observations are further confirmed, the availability of a disease
progression and a disease modification biomarker for HD should constitute a major
advance in the field. Indeed, the
development of drugs for the treatment of HD has been hampered by the lack of
sensitivity and precision of standard clinical end points. Similarly to other neurodegenerative diseases
such Alzheimer’s and Parkinson’s disease, clinical progression in HD is slow, erratic,
and relatively unpredictable at the individual level.

Beyond
the direct impact of this work, the approach used by Hu and colleagues seems to
signal a new trend in biomarker research: instead of limiting the scope of
biomarker research to the specific anatomical compartment primarily affected by
the disease, which in the case of the central nervous system is essentially
inaccessible, the field may significantly benefit from considering accessible
peripheral tissues which may display secondary pathobiology similar to that
affecting the primary tissues. Indeed, a
similar approach was used by Nardo and colleagues to identify a potential new protein
biomarker for Amyotrophic Lateral Sclerosis (PloS One October 5th; see
earlier post: New
Potential ALS Multiprotein Biomarker: Going Beyond Nerve Pathology)